
The 2,4-diamino pyrimidine moiety (1) is a common component in a variety of biologically active drug-like molecules. Pyrimidine derivatives have been found to be useful in the treatment of abnormal cell growth, such as cancer, in mammals. These moieties are commonly synthesized starting with pyrimidine intermediate 2 (where “X” is a leaving group; most commonly a halogen) and an equivalent of amine 3, HNR3R4 (see Scheme 1 below). For the vast majority of reactions involving pyrimidines of formula 2 and amines of formula 3, it is well known that this first amine addition occurs preferentially (or exclusively) at the more reactive pyrimidine 4-position (Chemistry of Heterocyclic Compounds, The Pyrimidines, Volume 52, Wiley, New York 1994, p. 371.) to provide intermediate 4. The primary factors that influence the selectivity of this initial amine addition are the stereoelectronic effects associated with substituents present in both pyrimidine 2 and amine 3 and to a lesser extent the reaction solvent. Subsequent heating of 4 with a second amine (5) provides the desired 2,4-diaminopyrimidine 1.

A representative example of the aforementioned chemistry can be found in WO00391901 and is highlighted in Scheme 2. Other examples utilizing this general synthetic scheme include Montebugnoli et. al. Tetrahedron 2002, (58), p. 2147. Chemistry of Heterocyclic Compounds, The Pyrimidines, Volume 52, Wiley, New York 1994, pp. 371–417. Selective amine addition to 2,4-dichloro-5-carboxamidopyrimidines is described in WO 02/04429. Selective amine additions to 2,4-dichloro-5-halopyrimidines are described in WO 01/65655.
While there are a number of general examples where specific pyrimidines (2), amines (3) or reaction conditions provide non-selective mixtures of the 2-chloro-4-amino-pyrimidine (4) and the isomeric 2-amino-4-chloro-pyrimidine (6) (Scheme 3), these reactions are of limited utility not only due to their lack of selectivity (and its impact on overall yield) but also because separation of the resulting isomers is generally extremely difficult. Preparative HPLC is generally required as a means to individually isolate the pure isomers (4 and 6), which can then be transformed further into compounds such as 1 or its isomer 7 respectively.

An example of such a reaction that provides mixtures of isomers is the addition of 4-methyl-aniline to 2,4-dichloro-5-trifluoromethylpyrimidine (Scheme 4). This electron deficient pyrimidine has a slight preference for amine addition to the pyrimidine 2-position. HPLC analysis of the crude reaction mixture shows a 1.4 to 1 mixture of and (4-Chloro-5-trifluoromethyl-pyrimidin-2-yl)-p-tolyl-amine (8) and (2-Chloro-5-trifluoromethyl-pyrimidin-4-yl)-p-tolyl-amine (9). Other examples of non-selective amine addition to 2,4 di-halogenopyrimidines are described in Chemistry of Heterocyclic Compounds, The Pyrimidines, Volume 52, Wiley, New York 1994, pp. 371–417. Luo et. al. Tetrahedron Lett. 2002, (43) p. 5739. Yoshida et. al. J. Chem. Soc, Perkin Trans. I: Organic and Bioorganic Chemistry, 1992 (7) p. 919. EP 647639 describes additions of piperidines to 2,4-dichloropyrimidine.

In contrast to the reactions described above, there are only a few very specific examples where an amine (3) is added to a pyrimidine of formula 2 in a selective manner to provide preferentially the 2-amino-4-chloro-pyrimidine 6. The most notable example of this type of reaction is the addition of N-methyl piperidine to 2,4-dichloro-5-methyl pyrimidine to provide 4-chloro-5-methyl-2-piperidinopyrimidine (Scheme 5) found in Yoshida et. al. J. Chem. Soc, Perkin Trans. I: Organic and Bioorganic Chemistry, 1992 (7) p. 919. In this case, the steric effect of the 5-methyl substituent on the pyrimidine coupled with the fact that the amine nucleophile is a tertiary (rather than a primary or secondary) amine provides for selective addition of piperidine to the pyrimidine 2-position.
